EMA publishes Q&A on Health Based Exposure Limits – Does the 1/1000 dose criterion come again into play in Cleaning Validation?

STR1

In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. This publication triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now a draft of a Q&A paper from the EMA provides some concretisation.

Image result for Cleaning Validation

http://www.gmp-compliance.org/enews_05736_EMA-publishes-Q-A-on-Health-Based-Exposure-Limits—Does-the-1-1000-dose-criterion-come-again-into-play-in-Cleaning-Validation_15560,15661,15963,Z-VM_n.html

In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. As mentioned in the publication itself, this document triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now, the draft of a question & answer paper from the European Medicines Agency provides some concretisation of the guideline.

The document altogether comprises five pages with 14 questions and answers.

The questions – and even more the answers – are very interesting, as shown in question 1 already: Do companies have to establish Health Based Exposure Limits (HBELs) for all products?

The answer is: Yes, but there are references to question 2 and 4 (and their respective answers). Question 2 clarifies what products/active substances are considered as highly hazardous. There are, among others, 5 groups listed, which products should be classified as highly hazardous (e.g.compounds with a high pharmacological potency, daily dose < 1 mg/day (veterinary dose equivalent 0.02 mg/kg)). For highly hazardous substances the answer yes in question 1 is expected. Even more interesting is the link to question and answer 4: Can calculation of HBELs be based on clinical data only (e.g. 1/1000th of the minimum therapeutic dose)? And the answer is yes, but only at designated circumstances. This means the products should have a favourable therapeutic index (safety window) and the pharmacological activity would be the most sensitive/critical effect.

Some further clarification regarding LD 50 is provided in Question 5 and the respective Answer: The use of LD 50 to determine health based limits is not allowed.

There are also more questions and answers regarding Veterinary Medicinal Products, the inspection of the competence of the toxicology expert developing HBELs, Occupational Exposure Limits, cleaning limits, Investigational Medicinal Products and paedric medicinal products and about Cross Contamination. Details will follow.

The document is still a draft and the industry has the opportunity to comment it until the end of April 2017. Let´s see what the final version will bring.

Please also see the draft Questions and answers on implementation of risk based prevention of cross contamination in production and ‘Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’on the EMA website.

At ECA´s Cleaning Validation Course, 9-10 February 2017 in Heidelberg, Germany the EMA Q&A draft will also be discussed.

some pics

Image result for Cleaning Validation
Image result for Cleaning Validation
Image result for Cleaning Validation
Image result for Cleaning Validation
Image result for Cleaning Validation
Image result for Cleaning Validation

///////////EMA, Q&A , Health Based Exposure Limits, 1/1000 dose , criterion,  Cleaning Validation,

Thailand Drug regulatory Update, Take a peep

STR1

http://www.fda.moph.go.th/eng/index.stm

[PDF]Regulatory Requirement for the Approval of generic Drug in Thailand …

Apr 13, 2014 – Thailand has its own drug registration format and also follows. ASEAN CTD. … Transparency in the regulatory authorities of member countries.

THAILAND PHARMACEUTICAL REGISTRATION AND APPROVAL

The Thai FDA (TFDA), one of several agencies under the Ministry of Public Health (MPH), is the regulatory body administering drugs in Thailand. The Drug Control Division of the TFDA is responsible for registration, licensing, surveillance, inspection and adverse event monitoring for all pharmaceuticals and pharmaceutical companies in Thailand. Foreign pharma companies dominate the Thai drug market. Due in part to trade negotiations, regional harmonization and positive economic trends, the pharmaceutical market in Thailand is predicted to double by 2022.There are several versions of the Drug Act currently in effect, and the Thai government is working on a revised version with updated regulations. Under the current laws, pharmaceuticals are categorized as either traditional or modern medicines, with different applications and oversight. Modern medicines are subdivided into three categories, each of which has separate registration requirements. Licenses currently do not require renewal.

STR2

Image result for thailand animated flag

STR1

link……….http://drug.fda.moph.go.th/eng/

FIRST ASEAN COUNTRY WITH A NATIONAL eCTD PROGRAM

News_2

Thai FDA intends to accept dossier in eCTD format: The Drug Regulatory Authority of Thailand (Thai FDA) has initiated the acceptance of Pilot eCTD from October 2014.Read More

eCTD requirements

http://drug.fda.moph.go.th/eng/files/2_eSubmission%20FAQ1_0921.pdf

http://drug.fda.moph.go.th/eng/files/1_TH%20Module%201%20and%20Regional%20Specification_0921_Tch.pdf

http://drug.fda.moph.go.th/eng/files/TH%20Regional%20Specification%20and%20Validation%20Criteria.pdf

STR1

STR1

Step to be followed to submit eCTD application

Taken from

https://www.linkedin.com/pulse/deep-dive-thai-ectd-overview-requirement-amar-tandon?trk=hp-feed-article-title-like

Regulatory Scientist at Kinapse

A) Prepare Application to get a eSubmission Identifier for every application issued. A request to the THAI FDA online service should be submitted to obtain an eSubmission identifier which will require following details.

  • Licensee Number
  • Description of Application
  • Dosage Form
  • INN or Generic Name
  • Strength
  • WHO ATC Code
  • Sequence Type
  • Application form
  • CPP (In case of Importer)

The eSubmission Identifier will be issued within 10 days of application. The Applicant must then make an appointment for submission within 30 days.

B) Prepare valid application along with validation reports as per country (Thailand) specific requirement with regional eSubmission Identifier provided.

The M1 requirements to be kept in consideration while compiling the Submission.

  • Enhanced granularity for each sections
  • Country code is not required in filenames
  • Information relating to orphan market is not mandatory
  • For LCM (Life cycle management) submissions the Operation attribute should be “Replace” in Tracking Table
  • Validation report should be submitted along with the sequence
  • 1.3.1 Product Information has been broken down into three specific sections for Labelling, SPC and the Package leaflet. No other product types are expected. If one file is submitted for this section, it should be submitted under 1.3.1.1 Labelling.
  • 1.3.1.3 Package Leaflet has been broken down into language sections for English, Thai and Other languages.
  • It is recommended that separate files should be submitted for each language.
  • Applicants can re-use the content submitted in other regions (including STF).
  • The identifier is a combination of a letter and seven digits.
  • Working documents are not needed and do not need to be provided within the eCTD framework for Thailand
  • Section 1.5.2 “Information for Generic, ‘Hybrid’ or Bio-similar Applications” has been broken down into three sections and given a section number to make expectations and cross referencing clearer.
  • Only one file should be provided for 1.6 Environmental Risk Assessment. It is not allowed to provide content in both 1.6.1 and 1.6.2.
  • During lifecycle, 1.8.2 Risk management plan should always use the lifecycle operator replace.

C) Dispatch Activity Delivery of the application at Thai FDA in CD/DVD (make an prior appointment with HA at drug_esubmissions@fda.moph.go.th

Thai FDA has proposed a set of media formats to be used while submission of eCTD

  • (CD-R) i.e. Compact Disc-Recordable
  • Digital Versatile Disc-Random Access Memory (DVD-RAM)
  • Digital Versatile Disc-Recordable (DVD+R/-R) recorded

Future Aspect-Import: The eCTD will be validated and imported into the THAI FDA Review System

Feedback: Application feedback (if there are problems experienced during the upload) and review of application by Thai FDA

Ensure that you do not use. 1. Double-sided discs 2. Re-writable disc (protection, authenticity and Stability of information cannot

Ensure that you do not use:

  • Double-sided discs,
  • Re-writable discs (protection, authenticity, and stability of information cannot be guaranteed)
  • Compressed or zipped files (except for validation reports)